title: Early growth response-1 (EGR-1) and nuclear factor of activated T cells (NFAT) cooperate to mediate CD40L expression in megakaryocytes and platelets.
abstract: Increasing evidence implicates circulating platelets as mediators of chronic inflammatory and autoimmune diseases via the expression and release of CD40L, an important modulator of inflammation and adaptive immune responses traditionally associated with activated T cells. Emerging evidence suggests that platelet CD40L is dynamically regulated in several chronic inflammatory and autoimmune diseases and may mediate progression and secondary pathology associated with those disease states. The present study identifies NFATc2 as a key transcriptional modulator of CD40L expression in megakaryocytes and inflammatory activity of platelets. Furthermore, the current data show that EGR-1, a member of the early growth response family of zinc finger transcription factors, modulates NFATc2-dependent regulation of CD40L expression in megakaryocytes. Our novel demonstration that in vivo biochemical or genetic inhibition of NFATc2 activity in megakaryocyte diminishes platelet CD40L implicates the NFATc2/EGR-1 axis as a key regulatory pathway of inflammatory and immunomodulatory activity in platelets and represents a target for the development of therapeutics for the potential treatment of chronic inflammatory and autoimmune diseases.
authors.affiliation: Department of Comparative Pathobiology, Purdue University School of Veterinary Medicine, West Lafayette, Indiana 47907; Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Crist
authors.affiliation: Department of Comparative Pathobiology, Purdue University School of Veterinary Medicine, West Lafayette, Indiana 47907; Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907.
authors.forename: Bennett D
authors.initials: BD
authors.lastname: Elzey
authors.affiliation: Department of Comparative Pathobiology, Purdue University School of Veterinary Medicine, West Lafayette, Indiana 47907.
authors.forename: Michelle T
authors.initials: MT
authors.lastname: Ahmann
authors.affiliation: Department of Comparative Pathobiology, Purdue University School of Veterinary Medicine, West Lafayette, Indiana 47907; Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907. Electronic address: scrist@purdue.edu.
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Ratliff
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000378:metabolism; D001792:Blood Platelets / Q000166:cytology / Q000378:metabolism*; D023201:CD40 Ligand / Q000096:biosynthesis* / Q000235:genetics; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D019169:Jurkat Cells; D020014:K562 Cells; D008533:Megakaryocytes / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; C494007:Nfatc2 protein, mouse; D023201:CD40 Ligand
keywords: Endothelial Cell; Inflammation; Megakaryocytes; Platelets; Signaling; Transcription